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“REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA” J Clin Oncol 25:579-586. © 2007 by American Society of Clinical Oncology Cheson et al, J Clin Oncol 17:1244, 1999 In 1999, an International Working Group (IWG) of clinicians, radiologists, and pathologists with expertise in the evaluation and management of patients with Lymphoma published guidelines for response assessment and outcomes measurement. Response Criteria for Lymphoma Definitions of End Points for Clinical Trials Standardized response criteria provide uniform end points for clinical trials: Allowing for comparisons among studies Facilitating the identification of more effective therapies The widely used IWG criteria for response assessment of lymphoma are based predominantly on CT. It became clear that the International Working Group criteria warranted revision, because of identified limitations and the increased use of : [18F] fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), flow cytometry, molecular biology “REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA” J Clin Oncol 25:579-586. © 2007 by American Society of Clinical Oncology The Competence Network Malignant Lymphoma convened an International Harmonization Project at which 5 subcommittees were formed: Response Criteria End Points for Clinical Trials Imaging Clinical Features Pathology/Biology Use of Positron Emission Tomography for Response Assessment of Lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma J Clin Oncol 25:571-578. © 2007 by American Society of Clinical Oncology PET- PET/CT PET using [18F]fluorodeoxyglucose (FDG, a radioactive derivative of glucose, is an advanced imaging tool, based on the increased glucose consumption of cancer cells), has emerged as a powerful functional imaging tool for staging, restaging, and response assessment of lymphomas. The advantage of PET over conventional imaging techniques, such as TC or RMN, is its ability to distinguish between viable tumor and necrosis or fibrosis in residual mass(es) often present after treatment. A recently developed integrated PET/CT system, which combines a PET camera and CT scanner in a single session, has overcome these drawbacks by providing both anatomical and functional imaging at the same position. PET/CT has become the new standard approach to imaging in the diagnosis and management of many cancer patients. Standardization of PET and CT Imaging Parameters Patients undergoing PET imaging should receive an FDG dose of 3.5 to 8 MBq/kg of body weight, with a minimum dose of 185 MBq in adults (5 mCi) and 18.5 MBq (0.5 mCi) in children. Patients should have fasted for at least 4 hours before FDG injection. Blood glucose level should not exceed 200 mg/dL at the time of FDG injection. If the blood glucose exceeds this level, the FDG-PET study should be rescheduled and an attempt made to control the blood sugar. Whole-body acquisition using a PET or PET/CT system should encompass at least the region between the base of the skull and themed thigh, and can be acquired in either two- or three-dimensional mode. Whole-body imaging should begin 50-70 minutes after the administration of FDG. The reconstructed PET or PET/CT images must be displayed on a computer workstation so that transaxial, sagittal, and coronal images can be viewed simultaneously. PET False-positive: - Thymic hyperplasia - Infection - Inflammation - Sarcoidosis - Brown fat Other causes of false-positive scans should be ruled out. False-negative: - Resolution of the equipment and technique - Variability of FDG avidity among histologic subtypes Juweid et al. evaluated the impact of integrating PET into the IWG criteria in a retrospective study of 54 patients with diffuse large B-cell NHL who had been treated with an anthracycline-based regimen. PET: Increased the number of complete remission (CR) patients, Eliminated the CRu category Enhanced the ability to discern the difference in progression-free survival (PFS) between patients experiencing CR and PR Recommendations for the use of PET or PET/CT PET is strongly recommended before treatment for patients with routinely FDG-avid, potentially curable lymphomas (eg, diffuse large B-cell lymphoma [DLBCL], Hodgkin’s lymphoma) to better delineate the extent of disease. 2. PET is essential for the post-treatment assessment of DLBCL and Hodgkin’s lymphoma because a complete response is required for a curative outcome. Based on the “meta-analysis by Zijlstra et al”, pooled sensitivity and specificity of FDG-PET for detection of residual disease after completion of first-line therapy were 84% and 90%, respectively, for HL, and 72% and 100%, respectively, for aggressive NHL. Recommendations for the use of PET or PET/CT 3. However, PET is recommended in the other, incurable histologies only if they were PET positive before treatment and if response rate is a primary end point of a clinical study. 4. Numerous studies have demonstrated that PET performed after 1 to 4 cycles of multiagent chemotherapy predicts therapeutic outcome; however, no currently available data demonstrate improvement in results by altering treatment based on this information. The role of PET for response assessment of aggressive NHL subtypes other than DLBCL and of indolent and mantle-cell lymphomas, is less clear. For these generally incurable NHLs, progression-free or overall survival is usually the primary end point in clinical trials evaluating their response to treatment. Requirement for Pretherapy PET Scan for Response Assessment of Lymphoma at the Conclusion of Therapy not obligatory for assessment of response after treatment of patients with HL, DLBCL, follicular lymphoma, or mantle-cell lymphoma because these lymphomas routinely are FDG avid. However, it is strongly encouraged for these subtypes because it can facilitate the interpretation of post-therapy PET. mandatory for variably FDG-avid lymphomas, if PET is used to assess their response to treatment. These include aggressive NHL subtypes other than DLBCL, such as T-cell lymphomas, and all subtypes of indolent NHL other than follicular lymphoma, such as extranodal marginal zone lymphoma of mucosa associated lymphoid tissue and small lymphocytic lymphoma. If PET is to be used for response assessment of patients with these histologic subtypes, there needs to be documentation that PET was positive at all disease sites ≥1.5 cm in diameter noted by CT. Timing of PET Performed for Response Assessment at the Conclusion of Therapy PET should not be performed before at least 3 weeks after chemotherapy and preferably 8 to 12 weeks after completion of radiotherapy. REVISED RESPONSE CRITERIA, 2007 End point Overall Survival is defined as the time from entry onto the clinical trial until death as a result of any cause. Progression Free Survival is defined as the time from entry onto a study until lymphoma progression or death as a result of any cause. PFS is often considered the preferred end point in lymphoma clinical trials, it reflects tumor growth, and therefore is interpretable earlier than the end point of overall survival. Event-Free Survival is measured from the time from study entry to any treatment failure including disease progression, or discontinuation of treatment for any reason (eg, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death). It may be useful in the evaluation of some therapies such as those that are highly toxic. Time to Progression is defined as the time from study entry until documented lymphoma progression or death as a result of lymphoma. Disease-Free Survival is measured from the time of occurrence of disease-free state or attainment of a CR to disease recurrence or death as a result of lymphoma or acute toxicity of treatment. End point Response Duratio is from the time when criteria for response (ie, CR or PR) are met, for which the event is the first documentation of relapse or progression. Lymphoma-Specific Survival (eg, disease-specific survival, cause specific survival) is defined as time from study entry to death as a result of lymphoma. Time to Next Treatment is defined as the time to next lymphoma treatment may be of interest, and is defined as time from the end of primary treatment until the institution of the next therapy. Clinical Benefit is one of the most important end points for patients as well as for drug approval by regulatory agencies has been evidence of clinical benefit. Clinical benefit may reflect improvement in: quality of life, reduction in patient symptoms, transfusion requirements, frequent infections, other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used in this end point. Follow-Up Evaluation - Good clinical judgment and a careful history - Physical examination - CBC and serum chemistries There is no evidence to support regular surveillance CT scans, given that the patient or physician identifies the relapse more than 80% of the time without the need for imaging studies. Data with PET are also insufficient to recommend routine procedures at this time. In a clinical trial, uniformity of reassessment is necessary to ensure comparability among studies with respect to the major end points of: event-free survival, disease-free survival progression free survival One recommendation has been to assess patients on clinical trials after completion of treatment at a minimum of every 3 months for 2 years, then every 6 months for 3 years, and then annually for at least 5 years. These intervals may vary with: - specific treatments - duration of treatment - protocols - unique drug characteristics Follow-Up Evaluation Recently, the National Comprehensive Cancer Network published recommendations for follow-up of patients with Hodgkin’s and NHL: for patients with Hodgkin’s lymphoma in an initial CR, an interim history and physical examination every 2 to 4 months for 1 to 2 years, then every 3 to 6 months for the next 3 to 5 years, with annual monitoring for late effects after 5 years. For follicular or other indolent histology lymphoma patients in a CR, the recommendation for follow-up was every 3 months for a year then every 3 to 6 months. For diffuse large B-cell NHL, the guidelines proposed follow-up every 3 months for 24 months then every 6 months for 36 months. CONCLUSION We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma The role of FDG PET in the management of lymphoma: what is the evidence base? Nuclear Medicine Communications. 28(5):335-354, May 2007. Kirby, Anna M.; Mikhaeel, N. George Abstract: [18F]Fluorodeoxyglucose positron emission tomography (18F-FDG PET) is playing an increasing role in the management of both Hodgkin and non-Hodgkin lymphoma, offering potential advantages in the accuracy of disease assessment at a number of points in the management pathway. This review evaluates the current level of confidence in the use of PET technology in: (1) initial staging, (2) the assessment of early response to chemotherapy, (3) the assessment of residual masses at completion of initial treatment, (4) follow-up, and (5) radiotherapy planning.